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Neuron. 2018 Mar 21;97(6):1235-1243.e5. doi: 10.1016/j.neuron.2018.02.013. Epub 2018 Mar 8.

ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.

Author information

1
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
3
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
6
RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
7
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
8
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
9
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.
10
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: orrxx002@umn.edu.

Abstract

Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.

KEYWORDS:

ATXN1; CIC; RAN translation; RNA toxicity; ataxia; cerebellum; neurodegeneration; polyglutamine; toxicity

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